In FY '97, LDRR was transferred from the Office of Director, NIH to the Clinical Center. The focus of our project is the use of magnetic resonance imaging (MRI) to understand the pathophysiology of multiple sclerosis (MS) and to determine whether disease activity is altered by treatment with Interferon Beta 1b (IFNB1b), Insulin-like Growth Factors (rhIGF-1), and Altered Peptide Ligand (APL). In the IFNB1b treatment trial, 33 MS patients were followed for a minimum of 2 years with the following observations: 1) The majority of patients treated with IFNB1b show an immediate decrease in the number of blood brain barrier openings (enhancing lesions). This effect of IFNB1b is not sustained, however, and after 24 months of treatment there is a steady increase in enhancing lesions. 2) Cumulative white matter disease or Bulk White Matter Lesion Load (BWMLL) was reduced by approximately 15 percent after 6 to 18 months of treatment and then increased despite the relatively low number of new lesions. 3) Cerebral atrophy which occurs at a rate of about 1 to 2 percent per year in untreated MS patients is prevented by IFNB1b during a period of 18 to 24 months. Magnetization Transfer (MT) imaging, which is sensitive to the amount of bound and free water in the white matter and indirectly reflects myelination, was also used to evaluate these patients. Whole brain histogram analysis of MT ratios in a cohort of MS patients showed that the histogram peak (Hp) of 0.25 ' 0.01 and histogram mean (Hm)=0.21 ' 0.01 were statistically lower than in control subjects with Hp of 0.27 ' 0.01 (p=0.008) and Hm of 0.23 ' 0.01 (p=0.016) respectively. When histograms were analyzed by quartiles, voxels with low MTR in Qrt 1 (MTR 0-0.124) increased during the baseline period and correlated with BWMLL (r=0.65). IFNB1b had no effect on MTR during the first 6 months of treatment. These results support the findings that IFNB1b acts primarily as a cytostatic agent in the brain and, despite a dramatic response by a decreasing number of contrast enhancing lesions, that the disease process probably continues at a subacute level. These findings appear to occur independent of whether an individual develops significantly elevated Neutralizing Antibodies (NAb) titers to IFNB1b. Only 4/11 patients who developed NAb had sustained elevated titers. Further studies are under way in a small cohort of MS patients to see if MRI-documented disease activity can be used to predict NAb development to biomodulating therapies.Two clinical MRI-based baseline-versus-treatment trials were started to evaluate the effect of rhIGF-1 (which stimulates oligodendrocyte proliferation) and the effect of APL (which is thought to interfere with the binding of T-cells to antigen presenting cells) on MR measures of disease activity. Phase II studies will be used to determine the effects of these drugs on contrast-enhancing lesion frequency as a primary outcome measure, with BWMLL and MTR histograms as secondary outcome measures.